The present invention relates to methods of generating pores in thin sheets of materials. More particularly, the invention relates to using a laser to drill uniform holes in thin flexible sheets of material comprised of polymers.
In various areas of technology it is desirable to make use of a thin sheet of material which has an array of regularly spaced, very small holes therein. For example, such might be used in the manufacture of various electronic components. Thin membranes which have one or more holes in them could also be used in the formation of components used in ink jet printers or fuel injectors. A more direct application of such a porous membrane is as a filter. The pore size and pore density could be adjusted to wide range of filter applications. Alternatively, liquid formulations containing a drug could be moved through such a porous member to create an aerosol for inhalation.
Aerosol therapy can be accomplished by aerosolization of a formulation (e.g., a drug formulation or diagnostic agent formulation) and administration to the patient, for example via inhalation. The aerosol can be used to treat lung tissue locally and/or be absorbed into the circulatory system to deliver the drug systemically. Where the formulation contains a diagnostic agent, the formulation can be used for diagnosis of, for example, conditions and diseases associated with pulmonary dysfunction.
In general, aerosolized particles for respiratory delivery must have a diameter of 12 microns or less. However, the preferred particle size varies with the site targeted (e.g., delivery targeted to the bronchi, bronchia, bronchioles, alveoli, or circulatory system). For example, topical lung treatment can be accomplished with particles having a diameter in the range of 1.0 to 12.0 microns. Effective systemic treatment requires particles having a smaller diameter, generally in the range of 0.5 to 6.0 microns, while effective ocular treatment is adequate with particles having a diameter of 15 microns or greater, generally in the range of 15-100 microns.
U.S. Pat. Nos. 5,544,646; 5,709,202; 5,497,763; 5,544,646; 5,718,222; 5,660,166; 5,823,178; 5,829,435; and 5,906,202 describe devices and methods useful in the generation of aerosols suitable for drug delivery. These devices generate fine, uniform aerosols by passing a formulation through a porous membrane having micron-scale pores as may be formed, for example, by laser ablation.
Porous membranes having such small features are difficult and costly to manufacture. Additionally, the pores must be of high quality and uniformity where they are to be used (1) in manufacturing electronic components; (2) in filter materials; (3) in ink jet printers; (4) in fuel injectors; and (5) to create aerosols for delivering therapeutic agents to patients to insure that the patients consistently receive the therapeutically required dose.
The porous membranes used in various applications are generally very thin, typically less than about a millimeter in thickness. The generation of micron-size holes is achieved by exposing the thin polymer material to a laser beam. Prior to laser drilling, the thin material is typically laminated onto a lid material. During the lamination process, wrinkles are frequently created in the film. The wrinkles frequently result in areas having a thickness greater than the depth of focus of the laser beam. As a consequence, a proportion of the pores drilled only partially penetrate these areas of the membrane. This lack of uniformity in pore formation severely compromises optimal operation of a device incorporating the film. For example, an aerosolization device having such a film incorporated therein requires excessive pressure to force a liquid formulation through the membrane, which can result in failure of the device.
The present invention provides improved methods of making thin porous membranes which do not suffer from the above-mentioned drawbacks, and devices incorporating the membranes.
Methods of generating pores in thin sheets of material, typically thin polymer films, are provided. The methods allow for generation of pores which uniformly penetrate the material. The method comprises laminating a thick film onto a thin film, then directing a laser source onto the thin film so as to form pores through the thin film. The increased stiffness conferred by the thick film reduces wrinkle formation in the thin film, resulting in uniform thickness of the thin film and consequent uniformity of pore depth. The pores may be formed either individually or simultaneously in one or more groups. The laser source may be controlled using a mask and/or beam-splitting and/or focusing techniques.
The invention further provides a method for generating pore structures in thin polymeric films comprising laminating a thick polymer film onto the thin polymer film, forming a laminate; placing the laminate onto a porous surface such that the thick film side of the laminate is adjacent to the porous surface; applying a vacuum to the porous surface, thereby holding the laminate onto the porous surface; and directing a laser source onto the thin film.
In one aspect of the invention, a neodymium-doped yttrium aluminum garnet (Nd:YAG) laser is used as the laser source.
In another aspect of the invention, an excimer laser is used as the laser source.
In still another aspect of the invention, the pores are formed so as to have an exit aperture of from about 0.5 to about 25 xcexcm in diameter.
In an additional aspect of the invention, a method of producing a nozzle for aerosolizing a formulation is provided wherein from about 200 to about 1,000 holes are formed in a membrane by projecting an excimer laser or focusing a YAG laser onto the membrane in a manner and for a time sufficient to ablate pores substantially through the membrane. In a particular embodiment, holes having an average relaxed exit aperture diameter of from about 0.5 to about 1.5 xcexcm and spaced from about 30 to about 70 xcexcm apart from each other can be formed in the membrane for the formation of particles for aerosol delivery to the respiratory tract.
The present invention further provides films made using the methods of the invention. These films can be used in a variety of devices. In one aspect of the invention, an extrusion nozzle, for use in an aerosolization device, comprising a thin film having pores that uniformly penetrate the thickness of the film is disclosed.
The present invention further provides a container for aerosolizing a flowable liquid formulation for delivery of the aerosolized formulation into a patient, which container comprises a porous membrane made according to a method of the invention. In some embodiments, the container is a blister packet. In some embodiments, the thick polymeric film serves as a barrier in the packet, and is removed just before extrusion of the drug formulation in the blister.
An advantage of the methods of the present invention lies in the property of the films generated by these methods that the majority of pores penetrate the thickness of the film. When these films are used in devices whose use entails extrusion of flowable substances under pressure through the pores, the amount of pressure required to force the flowable substance through the pores in the film is reduced, thereby enhancing the function, reliability, and longevity of the device. A further advantage is that aerosols generated by extruding a flowable formulation through a thin film made according to the methods of the invention are more uniform.
An advantage of the method of the invention is that pores can be formed in the membrane with a reduced number of pulses of applied laser energy.
An advantage of a blister packet made using the methods of the invention is that the thick polymeric film used in the process of generating pores in the thin film can also serve as a part of the blister packet, thereby eliminating the need for additional manufacturing steps.
These and other aspects, objects, features and advantages of the present invention will become apparent to those skilled in the art upon reading this disclosure in connection with the accompanying figure.